Autor: |
Barbero G; Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, Buenos Aires C1405, Argentina. barbero.gaston@maimonides.edu.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1425, Argentina. barbero.gaston@maimonides.edu., Castro MV; Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, Buenos Aires C1405, Argentina. castro.victoria@maimonides.edu.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1425, Argentina. castro.victoria@maimonides.edu., Villanueva MB; Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, Buenos Aires C1405, Argentina. villanueva.belen@maimonides.edu.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1425, Argentina. villanueva.belen@maimonides.edu., Quezada MJ; Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, Buenos Aires C1405, Argentina. majo_quezada@outlook.com.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1425, Argentina. majo_quezada@outlook.com., Fernández NB; Instituto de Biología y Medicina Experimental, Buenos Aires C1428, Argentina. natyfernandez24@gmail.com., DeMorrow S; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA. sharon.demorrow@austin.utexas.edu.; Department of Internal Medicine, Dell Medical School. The University of Texas at Austin, Austin, TX 78712, USA. sharon.demorrow@austin.utexas.edu.; Central Texas Veterans Healthcare System, Austin, TX 78712, USA. sharon.demorrow@austin.utexas.edu., Lopez-Bergami P; Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, Buenos Aires C1405, Argentina. lopezbergami.pablo@maimonides.edu.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1425, Argentina. lopezbergami.pablo@maimonides.edu. |
Abstrakt: |
Wnt5a signaling has been implicated in the progression of cancer by regulating multiple cellular processes, largely migration and invasion, epithelial-mesenchymal transition (EMT), and metastasis. Since Wnt5a signaling has also been involved in inflammatory processes in infectious and inflammatory diseases, we addressed the role of Wnt5a in regulating NF-κB, a pivotal mediator of inflammatory responses, in the context of cancer. The treatment of melanoma cells with Wnt5a induced phosphorylation of the NF-κB subunit p65 as well as IKK phosphorylation and IκB degradation. By using cDNA overexpression, RNA interference, and dominant negative mutants we determined that ROR1, Dvl2, and Akt (from the Wnt5a pathway) and TRAF2 and RIP (from the NF-κB pathway) are required for the Wnt5a/NF-κB crosstalk. Wnt5a also induced p65 nuclear translocation and increased NF-κB activity as evidenced by reporter assays and a NF-κB-specific upregulation of RelB, Bcl-2, and Cyclin D1. Further, stimulation of melanoma cells with Wnt5a increased the secretion of cytokines and chemokines, including IL-6, IL-8, IL-11, and IL-6 soluble receptor, MCP-1, and TNF soluble receptor I. The inhibition of endogenous Wnt5a demonstrated that an autocrine Wnt5a loop is a major regulator of the NF-κB pathway in melanoma. Taken together, these results indicate that Wnt5a activates the NF-κB pathway and has an immunomodulatory effect on melanoma through the secretion of cytokines and chemokines. |